The major emphasis of this work was the use of the SIV/macaque model of AIDS for the evaluation of potential vaccine strategies. The ability of whole inactivated SIV vaccine (WI-SIV) to modify subsequent disease course was assessed in a group of five immunized macaques challenged with cell-associated SIV. As predicted from previous experiments all macaques became infected; however, long-term evaluation showed that the immunized animals survived longer than the naive controls suggesting that immunization may beneficially modify the course of disease. Recombinants of the highly attenuated modified vaccinia virus of Ankara (MVA) expressing the SIVsmH4 gag-pol and env were generated. The immunogenicity and protective efficacy of the MVA recombinant (MVA-SIV) was compared with that of a similar recombinant in a Wyeth vaccinia virus background (Wyeth-SIV). Four animals were immunized with each recombinant virus a total of five times at approximately three month intervals. Whereas, the MVA-SIV boosted SIV antibody levels following sequential inoculations, the Wyeth-SIV recombinant only induced a boost after the second immunization and antibody levels declined subsequently. Thus, MVA-SIV appeared to more immunogenic than Wyeth-SIV. Although immunization did not prevent infection following intravenous challenge with uncloned SIVsm, the virus load of three of the four MVA-SIV- immunized animals was 100- to 1,000-fold reduced compared to animals immunized with nonrecombinant vaccinia virus. Also, plasma viremia was not detectable in the MVA-SIV group. Thus, immunization with MVA-SIV resulted in significant restriction of virus replication and dissemination which may be predictive of longterm survival of these animals.